Background: Dietary interventions are key for managing metabolic dysfunction–associated steatotic liver disease (MASLD), yet optimal diets and the role of PNPLA3 in modulating response to diet remain unclear. We evaluated the efficacy of a Mediterranean diet (MD) versus a low-fat diet (LFD) on hepatic fat and fibrosis, assessing interactions with PNPLA3 genotype. Methods: Two hundred fifty adults with MASLD with BMI ≥25 kg/m 2 were randomized to a 12-week moderately hypocaloric MD or LFD intervention. Individuals with excess alcohol intake and other etiologies of steatosis were excluded. Subjects were genotyped for PNLPA3 single-nucleotide polymorphism. Anthropometric measures, blood tests, and liver assessments [controlled attenuation parameter (CAP) and liver stiffness measurement (LSM)] were conducted at baseline and follow-up. Essential food items were provided, and adherence was tracked using validated questionnaires. The primary outcome was CAP, analyzed using linear mixed models adjusted for age and metabolic syndrome. Results: Both diets significantly reduced CAP, LSM, and body weight at follow-up, with no significant differences between groups. The mean difference between MD and LFD was −0.13 dB/m for CAP ( p =0.976, 95% CI: −8.54, 8.28), −0.19 kPa for LSM ( p =0.355, 95% CI: −0.58, 0.21), and 3.01 kg for weight ( p =0.159, 95% CI: −7.21, 1.19). PNPLA3 genotype did not significantly interact with diet for CAP, LSM, or weight ( p =0.286, p =0.464, p =0.622, respectively). Conclusions: Weight reduction achieved by MD and LFD is similarly efficient in steatosis and fibrosis reduction, while PNPLA3 genotype does not affect the response to diet. Further studies investigating the impact of diet and nutrigenetics on liver-related outcomes are warranted.